PROJECT SUMMARY/ABSTRACT Congenital heart disease is among the most common birth defects, affecting 1-2% of all live births. While surgical advances have dramatically improved survival, many patients face life-long neurological sequelae that substantially reduce quality of life. While postnatal medical factors may influence neurological outcome, recent fetal MRI data suggest that abnormal brain development begins in utero. Furthermore, cerebral maturity at birth predicts neurodevelopmental outcome. In utero neuroprotective therapies may reduce neurological sequelae for patients with certain forms of congenital heart disease. This proposal investigates factors influencing fetal brain development in congenital heart disease to give insight into rational methods for fetal neuroprotection. The proposal will address three key gaps in current knowledge: (1) the regional specificity and timing of onset of abnormal brain structure in congenital heart disease; (2) the physiological mechanisms that lead to abnormal fetal brain development; and (3) the fetal brain correlates of neurodevelopmental outcome. The study will employ innovative structural MRI techniques to address these aims, harnessing cutting edge MRI processing tools to correct for fetal motion to address one of the major limitations in fetal neuroimaging. Pregnant women will undergo fetal MRI twice during pregnancy, and after birth children will undergo neurodevelopmental testing at two years of age. The findings from this investigation will clarify mechanisms of abnormal brain development in congenital heart disease and inform development of fetal therapies to mitigate the neurological effects of congenital heart disease. This Mentored Patient-Oriented Career Development Award application aligns with the goals of the National Institute of Neurological Disorders and Stroke, as it will clarify abnormal brain development in this population and shed light on potential strategies to protect the brain. The proposal is also designed to provide important opportunities for training and career development to enable the candidate to become an independent investigator addressing neuroprotection in congenital heart disease. Dr. Rollins has experience in using neuroimaging tools to understand abnormalities in brain structure in congenital heart disease, and with this award, she will gain training in: (1) clinical epidemiology through a formal MPH curriculum; (2) clinical trial methods; and (3) advanced MRI techniques through practical laboratory exposure. She will benefit from an enormously rich cardioneurology and neuroimaging training environment, where she will develop skills in applying novel neuroimaging techniques to answer neurobiological questions. Ultimately, this research proposal and the accompanying training will provide a strong foundation for a successful independent research career devoted to minimizing the neurological sequelae of congenital heart disease.